Prostate cancer is the second leading cause of malignancy-related mortality in males in the Western world. While radical prostatectomy and local radiotherapy are largely successful for patients with localized cancer, available treatments for metastatic prostate carcinoma (PCa) have demonstrated weak curative efficacy. It is therefore necessary to find alternative therapeutic approaches to hormone-refractory metastatic prostate cancer. Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic PCa. The success of this approach depends on the ability of cytotoxic T cells to kill tumor cells. However, if the tumor environment exerts a suppressive action on antigen-specific tumor infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, successes. Thus, it is paramount to understand the cell biology of TIL and the modulation of TIL responses by the tumor environment.
The role of the prostate tumor environment in modulating T cell response have been analyzed with a study based on the use of collagen gel-matrix supported organ cultures of human PCa. The advantage of using this technique is that the microenvironment remains intact and all the factors that may affect TIL functions, such as cell-cell interaction, cell-matrix supported interaction and interstitial fluid, are preserved. This innovative approach to TIL biology allowed to obtain several important new findings.
In principle, TIL infiltrating PCa samples are mainly CD8+ T lymphocytes with an antigen-experienced, terminally differentiated phenotype (CD8+ CD45RA+ CD62L− CCR7−), positive for perforin and therefore able to kill the cancerous cells; however, they are in dormant state since they do not express activation markers such as CD25, CD69 and CD137. Moreover, different from normally responsive lymphocytes in tumor free prostates and peripheral blood, TIL are not activated locally by powerful signals acting either on TCR or downstream signaling pathways, indicating a tumor-restricted deficiency. In addition, evidence has been accumulating that arginase (ARG) and nitric oxide synthase (NOS) enzymes are over expressed in PCa as compared with hyperplasic prostate, with the intriguing observation that the tumor cells themselves rather than myeloid infiltrating cells could be the main source of the enzymes. The results indicate that the steady-state regulation of the dormant state is dependent on the enhanced intra-tumoral metabolism of the amino acid L-Arginine (L-Arg), since the simple addition of ARG and NOS specific inhibitors was sufficient to rouse these CTL, activate them and start a number of events leading to cytolitic granule polarization and killing of cognate targets. In addition, it has also been demonstrated the presence of high levels of nitrotyrosines in TILs, suggesting a local production of peroxynitrites, possibly due to ARG and NOS activities, since by inhibiting the activity of the enzymes a reduced tyrosine nitration was also achieved.
These results identify a mechanism by which human prostate cancer induces in situ immunosuppression. Thus, drug controlling the generation of reactive nitrogen species (RNS) might be useful to aid immunotherapeutic approaches for the treatment of cancer, by creating a favorable tumor environment for lymphocyte activation (Bronte et al., 2005).
Results from clinical trials have shown that the efficacy of different immunotherapeutic approaches is not adequate for an immediate and widespread transfer of this novel therapeutic approach to cancer patients. An important emerging concept is that the altered metabolism present in tumor microenvironment may have a profound impact on antitumor activity. Considering results mentioned above, it is clear that drugs controlling the generation of reactive nitrogen species (RNS) might enhance significantly the impact of immunotherapeutic approaches for the treatment of cancer. Accordingly, the present invention provides new furoxan compounds acting on the mechanisms of tumoral development.